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NeoPharm and Collaborators Present New IL13-PE38QQR Clinical Data In Brain Cancer

Posted on: 06/03/2003

NeoPharm and Collaborators Present New IL13-PE38QQR Clinical Data In Brain Cancer

Additional and New Preliminary Data From Three Separate Studies Unveiled At ASCO 39th Annual Meeting Provide Consistent Support for Further Development Of This Novel Approach

LAKE FOREST, Ill., June 3 /PRNewswire-FirstCall/ -- NeoPharm, Inc. (Nasdaq: NEOL) today announced that additional Phase I/II worldwide clinical trial data on IL13-PE38QQR, the Company's novel tumor-targeting agent for malignant glioma, were presented at the 39th Annual Meeting of the American Society of Clinical Oncology (ASCO), held in Chicago, IL from May 31-June 3, 2003. Two studies (Abstracts #403 and #405) were presented as poster discussions and the third (Abstract #476) was published in the 2003 ASCO Program Proceedings. These preliminary data represent a combined experience from more than 60 patients in various settings, including peri- and intra-tumoral delivery of IL13-PE38QQR for treatment of malignant glioma. The findings suggest consistent evidence of the tumor cytotoxic (cancer cell killing) effects of IL13-PE38QQR against malignant glioma tumor cells at a concentration as low as 0.125 micrograms/mL. Although not designed to address efficacy, encouraging survival results have been observed to beyond one year. Copies of NeoPharm's IL13-PE38QQR abstracts are available online at: .

"These data further support our commitment to develop IL13-PE38QQR for patients with malignant glioma," commented James M. Hussey, NeoPharm's President and Chief Executive Officer. "With plans underway to advance IL13- PE38QQR into pivotal Phase II/III clinical trials later this year, we will move one step closer to our goal of improving the outlook of people around the world combating this devastating disease."

IL13-PE38QQR has received orphan drug designation in Europe and the U.S., and fast track drug development program status from the U.S. Food and Drug Administration (FDA). NeoPharm has exclusively licensed IL13-PE38QQR from the National Cancer Institute and the FDA, and is developing the agent under a Cooperative Research and Development Agreement (CRADA) in collaboration with the laboratory of Raj K. Puri, MD, PhD, at FDA Center for Biologics Evaluation and Research (CBER).

Phase I/II IL13-PE38QQR Preliminary Findings

IL13-PE38QQR is currently under investigation in three ongoing Phase I/II clinical trials in patients with recurrent malignant glioma. The first IL13- PE38QQR clinical study is being conducted through the NCI Clinical Trial Evaluation Program (CTEP)-funded New Approaches to Brain Tumor Therapy (NABTT) Consortium. Johns Hopkins University Medical Center is the coordinating site for NABTT. Results from the initial 18 patients enrolled in this trial were presented as a poster discussion at ASCO (Abstract #405). These patients were all diagnosed with recurrent supratentorial malignant glioma. IL13-PE38QQR was administered by convection-enhanced delivery (CED) a new technique using positive pressure infusion to distribute therapeutic agents within brain tumors and in areas at risk for tumor spread. Two infusions were planned eight weeks apart without planned tumor resection. Patients were dosed with IL13-PE38QQR via two, intra-tumoral catheters at 200 microliters/catheter/hour for 96 hours (total 38.4 mL). The IL13-PE38QQR concentration is being increased in individual cohorts to determine the maximum tolerated dose (MTD). Six patients received IL-13PE38QQR at 0.125 micgorams/mL followed by three patients at each dose level of 0.25, 0.50, 1.0, and 2.0 micgorams/mL. Intra- tumoral infusion of the drug appears to be well tolerated in this population, permitting dose escalation and patient accrual to proceed. Similar adverse events occurred across all cohorts, with most being neurological or related to neurosurgical site. Tumor response, either microscopic or radiologic, has been observed in some patients. Enrollment is ongoing in this study.

The second clinical study presented as a poster discussion (Abstract #403) at ASCO described preliminary data from a clinical trial being conducted at six participating sites including Tel Aviv Sourasky Medical Center and Chaim Sheba Medical Center in Israel, University Hospital Eppendorf and University Hospital Kiel in Germany, and the Cleveland Clinic and the University of Colorado in the United States. This study is designed to determine the maximum tolerated dose (MTD) in terms of infusion duration and drug concentration of IL13-PE38QQR delivered by CED via one or two intratumoral catheters in patients with recurrent or progressive malignant glioma prior to planned tumor resection. Cohorts of 3-6 patients receive 0.50 micrograms/mL with escalating duration (4-7 days) to determine a MTD based on duration. After determination of maximum duration, drug concentration is escalated from 1.0-4.0 micrograms/mL in cohorts of 3-6 patients to determine a MTD based on concentration. Tumor necrosis at 6-13 days following infusion and proportion of patients surviving at 6 months is also assessed. Sixteen patients have been enrolled to date; comprising all four duration periods and two out of four concentration levels. Duration of infusion up to seven days and concentrations of 1.0 micrograms/mL appear to be safe and well tolerated. Evidence of tumor necrosis in some patients has also been observed. Pre- resection dose escalation continues as planned in this ongoing clinical study.

The third clinical study, published in the 2003 ASCO Program Proceedings (Abstract #476), involves several institutions including the University of California San Francisco (UCSF), M.D. Andersen Cancer Center (MDACC), Memorial Sloan-Kettering Cancer Center (MSKCC), and Yale University. Primary objectives of this study include, determination of the dose of IL13-PE38QQR that produce tumor cell death, referred to as the histologically effective concentration (HEC) and the corresponding drug toxicities following IL13- PE38QQR infusion into the tumor and areas adjacent to the tumor. Secondary objectives are the determination of time to tumor progression and patient survival. In Stage 1, patients receive drug intratumorally before (escalating concentrations) and peritumorally after (0.25 micrograms/mL, fixed) tumor resection. On Day 8 of Stage 1, en bloc tumor resection is performed to assess HEC and 2-3 peritumoral catheters are placed adjacent to the resection site in areas where residual tumor cells may be present. In Stage 2, the pre-resection infusion is eliminated and post-resection drug concentrations are escalated. In Stage 1, 15 patients were treated at escalating pre-resection concentrations (0.25, 0.50, 1.0, and 2.0 micrograms/mL). Histopathological (microscopic) analysis revealed tumor necrosis in most patients receiving concentrations of 0.5 micrograms/mL and higher. Five specimens had necrosis topographically related to the catheter in an ovoid zone extending up to 2.5 cm. All patients were able to complete the post-resection infusion at 0.25 micrograms/mL. The most frequently observed adverse events were headache (48%), sensory symptoms (29%), motor symptoms (24%), aphasia (19%), incoordination (19%), seizure (19%), fatigue (14%), confusion (14%) and hemiparesis (14%).

With confirmation of the HEC in Stage I, the pre-resection infusion was omitted and escalation of post-resection peritumoral infusion concentration began at 0.5 ug/ml in Stage 2. Stage 2 findings were recently presented during a plenary session of the American Association of Neurological Surgeons (AANS) 71st Annual Scientific Meeting and as a poster presentation at the 15th International Conference on Brain Tumor Research and Therapy. To date, a total of nine patients completed Stage 2 to determine the maximum tolerated infusion concentration (MTIC). All patients tolerated the peritumoral infusion and no dose limiting toxicities were observed for the six patients at 0.5 micrograms/mL. Two of three patients at 1.0 micrograms/mL developed symptomatic radiographic changes near the former catheter insertion location. As a result, 0.5 micrograms /mL was designated the MTIC post-resection. Enrollment of patients in Stage 3, to examine escalation of the infusion duration, is ongoing. While this trial was not designed to determine efficacy, clinical and radiographic follow-up has revealed survival without tumor progression of 3 to 90+ weeks. In addition, overall survival from time of treatment ranged from 12 to 90+ weeks (median 45 weeks).

For additional details regarding IL13-PE38QQR trial design, enrollment criteria and participating centers please refer to (keyword: IL13-PE38QQR).

Background Information

Malignant Glioma: The Disease

Malignant glioma, which includes glioblastoma multiforme and anaplastic astrocytoma tumors, is diagnosed in approximately 17,500 people in the U.S. annually and claims approximately the same number of lives each year. As there are very limited treatment options to prevent tumor progression, most people with glioblastoma multiforme usually live for less than one year after initial diagnosis, and less than six months after the first recurrence.

Mechanism of Action of IL13-PE38QQR

Malignant glioma cells, as compared to normal brain cells, express interleukin-13 (IL13) receptors at a high density. IL13 is an immune regulatory cytokine, or protein, secreted by cells. IL13-PE38QQR (a recombinant protein) is designed to detect and bind to IL13 receptors on the surface of malignant glioma cancer cells, and then selectively deliver a potent bacterial cytotoxic agent called PE38, derived from a bacteria called Pseudomonas aeruginosa, to destroy tumor cells while sparing healthy surrounding cells. In contrast, conventional, non-specific chemotherapeutic drugs attack abnormal cancer cells by stopping them from dividing and reproducing, but can also damage normal cells because these agents do not discriminate between cancerous and healthy cells. Futhermore, standard chemotherapy drugs are usually administered systemically, which leads to their distribution throughout the body rather than to one area, such as a tumor in the brain. Common chemotherapy side effects may occur when bone marrow is damaged and cannot produce enough red blood cells (causing weakness and fatigue), white blood cells (lowering the body's resistance to infections) or platelets (preventing blood from clotting properly, which can lead to excessive bleeding).

IL13-PE38QQR, on the other hand, is being developed as a highly specific tumor-targeting agent. It is administered directly to the tumor by positive- pressure CED, through catheters inserted in the tumor or brain surrounding the tumor, before and/or following surgical resection of the tumor. CED is designed to infuse IL13-PE38QQR directly to the tumor site and adjacent brain tissue to prevent recurrence of tumor cell growth. Investigators have sought to identify the optimum "therapeutic window" to provide patients with the safest, most effective dose at sufficient concentration to kill malignant cells while minimizing exposure to healthy brain tissue.

A mechanism of action study involving IL13-PE38QQR was published in the October 2002 issue of Molecular Cancer Therapeutics, a journal of the American Association for Cancer Research ( ). In a series of laboratory experiments designed to help define the molecular mechanisms for the therapeutic properties of IL13-PE38QQR, the authors provided evidence that human glioma tumor cells that express the IL-13 receptor undergo programmed cell death, or apoptosis, following intratumoral administration of IL13- PE38QQR, leading to regression of established tumors. IL13-PE38QQR appears to be tumor-selective and induces apoptosis, which persists after the drug is no longer detectable.

About NeoPharm

NeoPharm, Inc., based in Lake Forest, IL, is a publicly traded biopharmaceutical company dedicated to the research, development and commercialization of new and innovative cancer drugs for therapeutic applications. The Company has a broad portfolio of compounds in various stages of development.

Additional information about NeoPharm and recent news releases can be obtained by visiting NeoPharm's Website at: For copies of scientific abstracts related to IL13-PE38QQR from recent medical meetings, contact Lauren Greis, NeoPharm, at 847.295.8678.

Forward Looking Statements

This press release contains "forward-looking statements" within the meaning of Section 27A of the Securities Act of 1933 and Section 21E of the Securities Exchange Act of 1934. The Company has tried to identify such forward-looking statements by use of such words as "expects," "intends," "hopes," "anticipates," "believes," "could," "may," "evidences" and "estimates," and other similar expressions, but these words are not the exclusive means of identifying such statements. Such statements include, but are not limited to, any statements relating to the Company's drug development program and any other statements that are not historical facts. Such statements involve risks and uncertainties, including, but not limited to, those risks and uncertainties relating to difficulties or delays in development, testing, regulatory approval, production and marketing of the Company's drug candidates, uncertainty regarding the availability of third party lyophilization capacity, uncertainty regarding the outcome of damage claims made by or against the Company, including the outcome of the pending arbitration with Pharmacia, unexpected adverse side effects or inadequate therapeutic efficacy of the Company's drug candidates that could slow or prevent products coming to market, the uncertainty of patent protection for the Company's intellectual property or trade secrets and other risks detailed from time to time in filings the Company makes with the Securities and Exchange Commission including our annual reports on Form 10-K and our quarterly reports on Forms 10-Q. Such statements are based on management's current expectations, but actual results may differ materially due to various factors, including those risks and uncertainties mentioned or referred to in this press release. Accordingly, you should not rely on these forward-looking statements as a prediction of actual future results.

SOURCE NeoPharm, Inc.

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/CONTACT: Larry Kenyon, CFO, of NeoPharm, Inc., +1-847-295-8678; Investors, Janet Dally of MontRidge, LLC, +1-203-894-8038; or Media, Kristin Fayer of Outlook Marketing, +1-847-509-3099/

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